RU2048472C1 - METHOD SYNTHESIS OF (22R,S)-α-BUTYLIDENEDIHYDROXY-a-DIHYDROXYPREGNA-1,4-DIENE- -3,20-DIONE - Google Patents
METHOD SYNTHESIS OF (22R,S)-α-BUTYLIDENEDIHYDROXY-a-DIHYDROXYPREGNA-1,4-DIENE- -3,20-DIONE Download PDFInfo
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- RU2048472C1 RU2048472C1 SU905011922A SU5011922A RU2048472C1 RU 2048472 C1 RU2048472 C1 RU 2048472C1 SU 905011922 A SU905011922 A SU 905011922A SU 5011922 A SU5011922 A SU 5011922A RU 2048472 C1 RU2048472 C1 RU 2048472C1
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- dione
- diene
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- water
- methanol
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- 238000000034 method Methods 0.000 title claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 title abstract 3
- 238000003786 synthesis reaction Methods 0.000 title abstract 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 8
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims abstract description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract 3
- 238000001953 recrystallisation Methods 0.000 claims abstract 3
- 239000000047 product Substances 0.000 claims description 11
- SEKYBDYVXDAYPY-ILNISADRSA-N (8s,9s,10r,11s,13s,14s,16r,17s)-11,16,17-trihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-3-one Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 SEKYBDYVXDAYPY-ILNISADRSA-N 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 150000002430 hydrocarbons Chemical class 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 2
- -1 ligroin Chemical class 0.000 claims description 2
- 230000003993 interaction Effects 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract 2
- 239000002260 anti-inflammatory agent Substances 0.000 abstract 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract 1
- 239000000043 antiallergic agent Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 13
- 229960004436 budesonide Drugs 0.000 description 13
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/0026—Oxygen-containing hetero ring cyclic ketals
- C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0092—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by an OH group free esterified or etherified
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
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Abstract
Description
Изобретение относится к новому процессу изготовления (22R, S)-16α, 17α-бутилидендиокси-11β, 21-дигидроксипрегна-1,4- диен-3,20- диона(будезонида)
В соответствии с известным процессом, сущность которого раскрывается в [3] будезонид изготавливается путем реакции 16α-гидроксипреднизолона с бутаналом в диоксане в присутствии хлорной кислоты в качестве катализатора. Продукт реакции выделяют путем разбавления прореагировавшей смеси в хлориде метилена, нейтрализации посредством промывки в водном карбонате калия и воде и испарении растворителя с последующим процессом кристаллизации из эфира-лигроина. Затем продукт очищали посредством хроматографии, например, на установке "Сефадекс". Главные недостатки диоксана заключаются в его способности проникать сквозь защитные покрытия на кожу, образовывать перекиси. Другим недостатком известного процесса является применение хлорной кислоты, являющейся сильным окислителем, в результате чего ее применение в качестве катализатора сказывается в ухудшении качества выделения продукта реакции, а это затрудняет и удорожает последующий процесс очистки и обработки продукта. In accordance with the known process, the essence of which is disclosed in [3], budesonide is prepared by reacting 16α-hydroxyprednisolone with butanal in dioxane in the presence of perchloric acid as a catalyst. The reaction product is isolated by diluting the reacted mixture in methylene chloride, neutralizing it by washing in aqueous potassium carbonate and water and evaporating the solvent, followed by crystallization from ether-naphtha. The product was then purified by chromatography, for example, at a Sephadex unit. The main disadvantages of dioxane are its ability to penetrate protective coatings onto the skin and form peroxides. Another disadvantage of the known process is the use of perchloric acid, which is a strong oxidizing agent, as a result of which its use as a catalyst affects the quality of the isolation of the reaction product, and this complicates and increases the cost of the subsequent process of cleaning and processing the product.
Цель изобретения состоит в том, чтобы создать новый процесс, дающий более качественную реакцию выделения продукта и обеспечивающий более простую и более экономичную обработку и очистку продукта. The purpose of the invention is to create a new process that gives a better reaction of the selection of the product and provides a simpler and more economical processing and purification of the product.
Цель достигается тем, что процесс по изобретению осуществляется в ацетонитриле, а в качестве катализатора применяется р-толуолсульфокислота. The goal is achieved by the fact that the process according to the invention is carried out in acetonitrile, and p-toluenesulfonic acid is used as a catalyst.
Сочетание менее основного (по сравнению с диоксаном) растворителя ацетонитрила и обеднителя, например n-толуолсульфокислоты, дает более качественную реакцию выделения, упрощает и удешевляет процесс обработки и очистки продукта реакции по сравнению с известным процессом, в котором применяются диоксан и хлорная кислота. The combination of a less basic (compared to dioxane) solvent of acetonitrile and a depletion agent, for example, n-toluenesulfonic acid, gives a better reaction of isolation, simplifies and reduces the cost of processing and purification of the reaction product in comparison with the known process in which dioxane and perchloric acid are used.
Согласно предпочтительному примеру осуществления данного изобретения реакцию останавливают путем добавления воды и корректировки должным образом рН реагирующей смеси. Это можно сделать и путем добавления в воду водного карбоната гидрогенизованного натрия. После этого продукт кристаллизуется. Кристаллы отфильтровывают, растворяют в хлориде метилена и метаноле, а затем кристаллизуют путем добавления подходящего углеводорода типа лигроина, гексана, циклогексана или гептана, получая неочищенный продукт, который затем рекристаллизуется в метаноле воде с целью получения чистого будезонида. According to a preferred embodiment of the invention, the reaction is stopped by adding water and adjusting the pH of the reaction mixture appropriately. This can also be done by adding aqueous hydrogenated sodium carbonate to the water. After that, the product crystallizes. The crystals are filtered off, dissolved in methylene chloride and methanol, and then crystallized by the addition of a suitable hydrocarbon such as naphtha, hexane, cyclohexane or heptane to give a crude product, which is then recrystallized in methanol with water in order to obtain pure budesonide.
Процесс изготовления будезонида по изобретению состоит, таким образом, из двух стадий. The manufacturing process of the budesonide according to the invention thus consists of two stages.
Стадия 1. Изготовление неочищенного будезонида. Stage 1. The manufacture of crude budesonide.
16α-гидроксипреднизолон реагирует с бутаналом в ацетонитриле. В качестве катализатора добавляют n-толуолсульфоновую кислоту. Реакционную смесь разбавляют водой и водным карбонатом гидрогенизованного натрия. После охлаждения до 5-15оС кристаллизовавшийся продукт отфильтровывают и промывают водой. Затем влажную или сухую среду фильтрата растворяют в хлориде метилена. Если вещество используется во влажном виде, то образовавшуюся при растворении водную фазу удаляют. Добавляют метанол и осаждают результирующий неочищенный будезонид путем добавки лигроина или другого подходящего углеводорода (например, гексана, гептана или циклогексана), после чего неочищенный будезонид отфильтровывают.16α-hydroxyprednisolone reacts with butanal in acetonitrile. As a catalyst, n-toluenesulfonic acid is added. The reaction mixture was diluted with water and aqueous hydrogenated sodium carbonate. After cooling to 5-15 ° C., the crystallized product is filtered off and washed with water. The wet or dry filtrate medium is then dissolved in methylene chloride. If the substance is used in wet form, then the aqueous phase formed during dissolution is removed. Methanol is added and the resulting crude budesonide is precipitated by the addition of naphtha or other suitable hydrocarbon (e.g. hexane, heptane or cyclohexane), after which the crude budesonide is filtered off.
Стадия 2. Изготовление чистого будезонида. Stage 2. Production of pure budesonide.
Неочищенный будезонид растворяют в метаноле при температуре около 60оС. Раствор фильтруют сквозь плотный фильтр и кристаллизуют продукт путем добавки воды. После охлаждения до температуры 5-20оС, фильтрации и промывки в метаноле воде, будезонид сушат в вакууме при температуре 40-45оС. Этот процесс проще, гораздо экономичнее и менее опасен для здоровья, чем известный процесс.The crude budesonide is dissolved in methanol at a temperature of about 60 about C. The solution is filtered through a dense filter and the product crystallizes by adding water. After cooling to 5-20 ° C, filtering and washing with methanol in water the budesonide is dried in vacuum at 40-45 C. This process is simpler, more economical and less hazardous to health than known process.
Рабочий пример. Реакцию выполняют в атмосфере азота. 15,4 г n-толуолсульфоновой кислоты растворяют в 200 мл ацетонитрила. В раствор добавляют 50,0 г 16α-гидроксипреднизолона и 17,6 мл бутанала. Температура увеличивается до 25оС. Через 30 мин растворяется большинство материала. Вскоре после этого продукт начинает кристаллизоваться. Через 3 ч реакцию останавливают путем добавления 75 мл насыщенного водного раствора карбоната гидрогенизованного натрия, в результате чего кристаллизуется продукт. Высушенный продукт растворяют в хлориде метилена и метаноле и кристаллизуют путем добавления лигроина (барометрическое давление 40-65), получая неочищенный будезонид.Working example. The reaction is carried out in a nitrogen atmosphere. 15.4 g of n-toluenesulfonic acid are dissolved in 200 ml of acetonitrile. 50.0 g of 16α-hydroxyprednisolone and 17.6 ml of butanal are added to the solution. The temperature rises to 25 about C. After 30 minutes, most of the material is dissolved. Soon after, the product begins to crystallize. After 3 hours, the reaction is stopped by adding 75 ml of a saturated aqueous solution of hydrogenated sodium carbonate, whereby the product crystallizes. The dried product is dissolved in methylene chloride and methanol and crystallized by the addition of naphtha (barometric pressure 40-65), obtaining the crude budesonide.
Неочищенный будезонид рекристаллизуют из метанола воды, получая чистый будезонид с соотношением изомеров A B≈1 1 (определено методом жидкостной хроматографии высокого давления), [α] 25 100,0о (с 0,2; СН2Cl2); M+ 430 (теоретическое значение 430,5).The crude budesonide is recrystallized from methanol of water to obtain pure budesonide with an isomer ratio of AB≈1 1 (determined by high pressure liquid chromatography), [α] 25 100.0 about (with 0.2; CH 2 Cl 2 ); M + 430 (theoretical value of 430.5).
Claims (3)
взаимодействием 11β, 16α, 17α, 21 -тетрагидроксипрегна-1,4-диен-3,20-диона формулы
с бутаналом CH3CH2CH2CHO в среде растворителя в присутствии катализатора, отличающийся тем, что реакцию ведут в ацетонитриле с использованием в качестве катализатора п-толуолсульфокислоты.The method of obtaining (22R, S) - 16α, 17α butylidenedioxy-11β, 21-dihydroxypregna-1,4-diene-3,20-dione of the formula
the interaction of 11β, 16α, 17α, 21-tetrahydroxypregna-1,4-diene-3,20-dione of the formula
with butanal CH 3 CH 2 CH 2 CHO in a solvent medium in the presence of a catalyst, characterized in that the reaction is carried out in acetonitrile using p-toluenesulfonic acid as a catalyst.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8903219A SE8903219D0 (en) | 1989-10-02 | 1989-10-02 | PROCESS FOR THE MANUFACTURE OF BUDESONIDE |
| SE8903219-7 | 1989-10-02 | ||
| PCT/SE1990/000619 WO1991004984A1 (en) | 1989-10-02 | 1990-09-27 | Process for the manufacture of budesonide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| RU2048472C1 true RU2048472C1 (en) | 1995-11-20 |
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ID=20377019
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SU905011922A RU2048472C1 (en) | 1989-10-02 | 1990-09-27 | METHOD SYNTHESIS OF (22R,S)-α-BUTYLIDENEDIHYDROXY-a-DIHYDROXYPREGNA-1,4-DIENE- -3,20-DIONE |
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|---|---|
| US (1) | US5556964A (en) |
| EP (1) | EP0494942B1 (en) |
| JP (1) | JP2965352B2 (en) |
| KR (1) | KR0160527B1 (en) |
| AT (1) | ATE130310T1 (en) |
| AU (1) | AU632864B2 (en) |
| BG (1) | BG61608B1 (en) |
| BR (1) | BR9007700A (en) |
| CA (1) | CA2065861C (en) |
| CY (1) | CY2084B1 (en) |
| DE (1) | DE69023664T2 (en) |
| DK (1) | DK0494942T3 (en) |
| ES (1) | ES2079491T3 (en) |
| FI (1) | FI103204B1 (en) |
| HK (1) | HK52097A (en) |
| HU (1) | HU212576B (en) |
| LT (1) | LT3697B (en) |
| LV (1) | LV10283B (en) |
| NO (1) | NO178827C (en) |
| RO (1) | RO110947B1 (en) |
| RU (1) | RU2048472C1 (en) |
| SE (1) | SE8903219D0 (en) |
| SG (1) | SG43344A1 (en) |
| UA (1) | UA26860C2 (en) |
| WO (1) | WO1991004984A1 (en) |
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| US6166024A (en) | 1995-03-30 | 2000-12-26 | Mayo Foundation For Medical Education And Research | Use of topical azathioprine and thioguanine to treat colorectal adenomas |
| IT1291288B1 (en) | 1997-04-30 | 1999-01-07 | Farmabios Srl | PROCESS FOR THE PREPARATION OF 16,17 ACETALS OF PREGNAN DERIVATIVES WITH CONTROL OF THE EPIMERICAL DISTRIBUTION AT C-22. |
| SE9704186D0 (en) | 1997-11-14 | 1997-11-14 | Astra Ab | New composition of matter |
| US6266556B1 (en) | 1998-04-27 | 2001-07-24 | Beth Israel Deaconess Medical Center, Inc. | Method and apparatus for recording an electroencephalogram during transcranial magnetic stimulation |
| FR2782823B1 (en) | 1998-09-01 | 2000-11-17 | Neopost Ind | THERMAL PRINTING PROCESS |
| US6234167B1 (en) | 1998-10-14 | 2001-05-22 | Chrysalis Technologies, Incorporated | Aerosol generator and methods of making and using an aerosol generator |
| US6491233B2 (en) | 2000-12-22 | 2002-12-10 | Chrysalis Technologies Incorporated | Vapor driven aerosol generator and method of use thereof |
| US6701921B2 (en) | 2000-12-22 | 2004-03-09 | Chrysalis Technologies Incorporated | Aerosol generator having heater in multilayered composite and method of use thereof |
| US6501052B2 (en) | 2000-12-22 | 2002-12-31 | Chrysalis Technologies Incorporated | Aerosol generator having multiple heating zones and methods of use thereof |
| US6799572B2 (en) | 2000-12-22 | 2004-10-05 | Chrysalis Technologies Incorporated | Disposable aerosol generator system and methods for administering the aerosol |
| US6681998B2 (en) | 2000-12-22 | 2004-01-27 | Chrysalis Technologies Incorporated | Aerosol generator having inductive heater and method of use thereof |
| US20030055026A1 (en) * | 2001-04-17 | 2003-03-20 | Dey L.P. | Formoterol/steroid bronchodilating compositions and methods of use thereof |
| US6568390B2 (en) | 2001-09-21 | 2003-05-27 | Chrysalis Technologies Incorporated | Dual capillary fluid vaporizing device |
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| SE8604059D0 (en) * | 1986-09-25 | 1986-09-25 | Astra Pharma Prod | A METHOD OF CONTROLLING THE EPIMERIC DISTRIBUTION IN THE PREPARATION OF 16,17-ACETALS OF PREGNANE DERIVATIVES |
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- 1990-09-27 WO PCT/SE1990/000619 patent/WO1991004984A1/en active IP Right Grant
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- 1990-09-27 RO RO92-200446A patent/RO110947B1/en unknown
- 1990-09-27 UA UA94010159A patent/UA26860C2/en unknown
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- 1990-09-27 RU SU905011922A patent/RU2048472C1/en active
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